Written By Rizki A. Noviar on Friday, September 27, 2013 | 03:42

Indonersia - A single-center, randomized trial testing metformin on top of
statins in nondiabetic subjects in the hopes of slowing or halting
the progression of cardiovascular disease has come up empty-handed.

But Dr David Preiss (University of Glasgow, Scotland), presenting the Carotid Atherosclerosis: Metformin For Insulin Resistance (CAMERA) trial results here yesterday,
said that "impressive" weight loss seen in the metformin group—one of
the trial's secondary end points—is worth exploring further.

CAMERA randomized 173 subjects with established coronary disease and a
large waist circumference, but no diabetes, to either metformin 850 mg
twice daily or placebo.

As Preiss explained to heartwire , the rationale for the study came from previous observations, including the UKPDS study, that metformin reduced not only
diabetes end points, but also MI. Moreover, the CVD benefits appeared to
be unrelated to glycemic improvement.

In CAMERA, investigators saw glycemia levels drop over the trial's
18-month follow-up in the metformin-treated group, as expected. But for
the primary end point of carotid intima-media thickness (CIMT),
Preiss and colleagues saw absolutely no differences between groups.
Carotid plaque score, the main secondary outcome, was also no
different between groups.

In retrospect, Preiss commented to heartwire, the choice of CIMT for the primary end point, as a surrogate for CVD, was not ideal.

"I'm not a diabetologist, but if any group of physicians should be
cautious about a study with surrogate markers, you'd think it would be
these guys," Preiss mused.

Other surrogate measures of CVD also showed no benefit of metformin,
including total cholesterol, HDL, and non-HDL. Very "marginal"
differences in triglycerides and high-sensitivity C-reactive protein
(hs-CRP) favored the metformin group, but these were "not impressive,"
Preiss commented.

The story for metabolic end points was slightly different, however.
CAMERA did show "quite an impressive fall in weight," Preiss said—a
difference of 3.2 kg between groups. There were also significantly
greater declines in body-mass index (BMI) in the metformin group.

To heartwire, Preiss agreed the CIMT results were
disappointing, but given the lack of differences in other CVD markers, a
change in CIMT in the absence of cholesterol improvement "would
have been a big surprise, and hard to explain."

The question of whether the weight change and potentially the signal
of anti-inflammatory benefits with metformin will translate into a
reduction in hard cardiovascular disease end points may be answered
by forthcoming trials.

The GLINT study, now under way, is a multicenter CV
primary-prevention trial with a planned enrollment of 12 000
nondiabetic subjects. Participants will have to have a predicted 10-year
risk of CVD of 20% (by Framingham) and a high-normal HbA1c; they are being randomized to either metformin or placebo, with a follow-up of five years.

Two smaller studies may also provide some insights: REMOVAL is a 500-patient, multinational study
looking at add-on metformin in type 1 diabetes, with an end point of
change in CIMT. Another is GIPS III, a Dutch study of 380 post-STEMI patients, looking at the ability of metformin to reduce progression to heart failure.

So more answers on metformin in CVD are coming, Preiss said. "You
wouldn't dismiss its chances [of succeeding] based on our study alone,"
he said.

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